The neurodegenerative diseases ? Alzheimer?s Disease (AD), Parkinson?s Disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and others ? together constitute one of the most significant unmet challenges in human health, affecting greater than 50 million people worldwide with no treatments to slow or stop progression. With the advent of the genomewide association study (GWAS) in 2005, and the subsequent identification of hundreds of common variant risk factors for AD, PD, FTD, and ALS, we have many loci that may translate into new targets for therapeutic intervention. To date, however, few mechanistic studies have been performed as follow-up to these GWAS-generated leads. One exception to this general rule has been with respect to the 7p21 locus we and others reported in 2010 to confer risk for the AD-related dementia FTD. In the first five years of this R01, we used a combination of computational and bench-based approaches to definitively establish the expression quantitative trait locus (eQTL) relationship between GWAS-identified single nucleotide polymorphisms (SNPs) and expression of the target gene TMEM106B. We furthermore defined the causal genetic variant at this locus, its CTCF-based mechanism for altering expression of TMEM106B, and the deleterious effects on lysosomal pathways of altering TMEM106B expression. We coupled these mechanistic experiments with investigations of the genetic modifier effects of TMEM106B genotype in FTD due to C9orf72 hexanucleotide expansions. Thus, through our work and the work of others, the field has gained an understanding of the pathways through which genetic risk at 7p21 is conferred, and the groups of patients in which targeting of TMEM106B may be viable therapeutically. In this RO1 renewal application, we propose to deepen our understanding of TMEM106B biology, investigating its influence in multiple neurodegenerative diseases, and elucidating its role in lysosomal function and cellular health. Specific Aim 1: Determine whether genetic modifier effects of the GWAS-identified FTD common variant risk factor TMEM106B extend across a spectrum of neurodegenerative diseases. We will investigate TMEM106B genotype effects in >1300 longitudinally-followed AD, PD, FTD, and ALS patients. We will determine whether TMEM106B acts as a genetic modifier in PD associated with GBA mutations. Specific Aim 2: Elucidate the mechanisms by which changes in TMEM106B expression affect lysosomal- autophagy pathway function and cellular health. We will follow-up preliminary work demonstrating that TMEM106B may affect autophagosome-lysosome fusion through a VAMP8-Syntaxin17 pathway. We will investigate TMEM106B-induced changes in lysosomal acidification through direct measurement of ion conductances across the lysosomal membrane and investigations of TMEM106B?s role in assembly of the vacuolar ATPase.